In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 1264-1264
Abstract:
Galectins are a family of animal lectins, which bind beta-galactose moieties. Gal3 is the only chimeric family member of Gals and consists of a collagen-like N-terminal region and a C-terminal carbohydrate recognition domain (CRD), which has binding affinity for galactose and N-acetyl-lactosamine. Gal3 is known to be secreted through Golgi apparatus-independent alternative pathway. Previously, we found that stimuli-induced p53 activation induced bystander killing effect against adjacent cells. This p53 bystander effect is mediated through the secretion of Gal3 with the requirement of p53-dependent induction of tumor suppressor activated pathway-6 (TSAP6). We found the apoptotic activity of extracellular Gal3: a variety of tumor cell types (malignant glioma, breast, colon, prostate, lung) are sensitive to Gal3-mediated killing, while normal cells (fibroblast, endothelial) are not affected. We demonstrated that conditional sGal3 induction (tet-on system) in glioma xenografts strongly inhibits tumor growth without overt toxicity in mice. We found that Gal3-mediated tumor cell killing was neutralized with lactose, a Gal3-CRD binding ligand, and Gal3-mediated apoptosis was inhibited by treatment with a caspase 9 inhibitor (LEHD) but not by a caspase 8 inhibitor (IETD). Gal3 interacts with several glycosylated cell surface proteins. We identified that Gal3-induced tumor specific apoptosis is mediated through Gal3-beta1 integrin binding through GST-Gal3 pulldown assay, cell membrane-specific Gal3-beta1 integrin co-immunoprecipitation, and beta1 integrin siRNA neutralization. Further, the treatment of N-glycosylation inhibitor (tunicamycin) interfered with Gal3-beta1 integrin interaction whereas, O-glycosylation inhibitor (benzyl-O-N-acetyl-D-galactosamine) increased N-glycosylation of beta1 integrin as well as consequent Gal3-beta1 integrin interaction and Gal3-mediated apoptosis. In summary, our data demonstrate that extracellular Gal3 interacts with tumor cells through highly-glycosylated cell surface beta1 integrin through its CRD binding and consequently induces apoptosis. These findings are important for our understanding of tumor-specific killing of Gal3 and suggest that Gal3 can be exploited as a therapeutic agent for cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1264.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-1264
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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